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This study utilizes a national longitudinal sample of US adults from early to middle adulthood to explore the time and genetic dynamics of the influences of family instability (change in parental figures in childhood) on adulthood depression. Using mixed effects model with autocorrelated error structure, this study provides three-fold empirical findings. First, we found that both addition and loss of parental figures are positively related to depression throughout early and middle adulthood. Second, we are the first to found that genetic sensitivity toward depression exaggerates the negative association between entry into intact families and depression, but the moderation effect is constant across time. Third, we found that transition from stepfamilies into single-parent families are positively related to early adulthood depression, though the effect declines in middle adulthood. The results reveal the time-complexity in the long-term impacts of family instability and imply that genetic sensitivity contributes to the health inequality caused by family instabilities.